In this application, we propose to study the role of TRL9 in immune and islet beta cell function and diabetes. Our preliminary data suggest that TLR9 deficient mice have enhanced islet beta cell function and are resistant to type 1 diabetes development and high fat diet induced obesity. We propose to investigate this novel finding and believe that once we understand the basic mechanisms of how TLR9 regulates beta cell function, we will be able to provide better knowledge to the public and hopefully to design better preventive and/or therapeutic strategies. We propose 3 specific aims to achieve this goal: 1): We hypothesize that TLR9 antagonists will improve beta cell development and function, and therefore, will have preventive and/or therapeutic effects on T1D development. To test this hypothesis, we will treat mice with a TLR9 antagonist and study the effect on diabetes development. 2): We hypothesize that TLR9 plays a role in obesity and T2D development. We will test this hypothesis by investigating the function of immune cells, adipocytes and islet beta cells using a high fat induced obesity (HFIO) model. We also hypothesize that TLR9 antagonists will improve the function of these cells and beta cell development and will have preventive and/or therapeutic effects on obesity and T2D development. We will test this hypothesis by treating wild type mice with a TLR9 antagonist and study the effect on obesity and T2D development. 3): We hypothesize that restoration of TLR9 in immune and islet beta cells will reverse the phenotype seen in TLR9-/- mice. To test our hypothesis, we will introduce TLR9 as a transgene in our TLR9 deficient mice under cell specific promoters. We will study the functions of immune and islet beta cells and the effect on diabetes development in these mice.